Clinical management of cUTI, cIAI, and HABP/VABP attributable to carbapenem-resistant Gram-negative infections in Spain

Carbapenemasa; Infeccions gramnegatives; Infeccions associades a l'assistència sanitàriaCarbapenemasa; Infecciones gramnegativas; Infecciones asociadas a la asistencia sanitariaCarbapenemase; Gram-negative infections; Healthcare-associated infectionsIntroduction. Carbapenem-resistant Gram-negative (CRGN) infections are a major public health problem in Spain, often implicated in complicated, healthcare-associated infections that require the use of potentially toxic antibacterial agents of last resort. The objective of this study was to assess the clinical management of complicated infections caused by CRGN bacteria in Spanish hospitals. Methods. The study included: 1) a survey assessing the GN infection and antibacterial susceptibility profile in five participating Spanish hospitals and 2) a non-interventional, retrospective single cohort chart review of 100 patients with complicated urinary tract infection (cUTI), complicated intra-abdominal infection (cIAI), or hospital-acquired bacterial pneumonia/ventilator-associated bacterial pneumonia (HABP/VABP) attributable to CRGN pathogens. Results. In the participating hospitals CRGN prevalence was 9.3% amongst complicated infections. In the retrospective cohort, 92% of infections were healthcare-associated, and Klebsiella pneumoniae and Pseudomonas aeruginosa were the most common pathogens. OXA was the most frequently detected carbapenemase type (71.4%). We found that carbapenems were frequently used to treat cUTI, cIAI, HABP/VABP caused by CRGN pathogens. Carbapenem use, particularly in combination with other agents, persisted after confirmation of carbapenem resistance. Clinical cure was 66.0%, mortality during hospitalization 35.0%, mortality at the time of chart review 62.0%, and 6-months-post-discharge readmission 47.7%. Conclusion. Our results reflect the high burden and unmet needs associated with the management of complicated infections attributable to CRGN pathogens in Spain and highlight the urgent need for enhanced clinical management of these difficult-to-treat infections.Funding for this research was provided by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA

Clinical management of cUTI, cIAI, and HABP/VABP attributable to carbapenem-resistant Gram-negative infections in Spain

Introduction. Carbapenem-resistant Gram-negative (CRGN) infections are a major public health problem in Spain, often implicated in complicated, healthcare-associated infections that require the use of potentially toxic antibacterial agents of last resort. The objective of this study was to assess the clinical management of complicated infections caused by CRGN bacteria in Spanish hospitals. Methods. The study included: 1) a survey assessing the GN infection and antibacterial susceptibility profile in five participating Spanish hospitals and 2) a non-interventional, retrospective single cohort chart review of 100 patients with complicated urinary tract infection (cUTI), complicated intra-abdominal infection (cIAI), or hospital-acquired bacterial pneumonia/ventilator-associated bacterial pneumonia (HABP/ VABP) attributable to CRGN pathogens. Results. In the participating hospitals CRGN prevalence was 9.3% amongst complicated infections. In the retrospective cohort, 92% of infections were healthcare-associated, and Klebsiella pneumoniae and Pseudomonas aeruginosa were the most common pathogens. OXA was the most frequently detected carbapenemase type (71.4%). We found that carbap enems were frequently used to treat cUTI, cIAI, HABP/VABP caused by CRGN pathogens. Carbapenem use, particularly in combination with other agents, persisted after confirmation of carbapenem resistance. Clinical cure was 66.0%, mortality during hospitalization 35.0%, mortality at the time of chart review 62.0%, and 6-months-post-discharge readmission 47.7%. Conclusion. Our results reflect the high burden and un met needs associated with the management of complicated infections attributable to CRGN pathogens in Spain and highlight the urgent need for enhanced clinical management of these difficult-to-treat infections.Funding: Funding for this research was provided by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA

Activity of imipenem/relebactam against Enterobacterales and Pseudomonas aeruginosa in Spain. SMART 2016-2020

Objectives. To determine susceptibility to the novel β-lactam/β-lactamase inhibitor combination imipenem/relebactam in clinical isolates recovered from intra-abdominal (IAI), urinary (UTI), respiratory (RTI) and bloodstream (BSI) infections in the SMART (Study for Monitoring Antimicrobial Resistance Trends) study in SPAIN during 2016 – 2020. Methods. Broth microdilution MICs for imipenem/relebactam and comparators were determined by a central laboratory against isolates of Enterobacterales and Pseudomonas aeruginosa. MICs were interpreted using EUCAST-2021 breakpoints. Results. In total, 5,210 Enterobacterales and 1,418 P. aeruginosa clinical isolates were analyzed. Imipenem/relebactam inhibited 98.8% of Enterobacterales. Distinguishing by source of infection susceptibility was 99.1% in BSI, 99.2% in IAI, 97.9% in RTI, and 99.2% in UTI. Of intensive care unit isolates (ICU) 97.4% were susceptible and of non-ICU isolates 99.2% were susceptible. In Enterobacterales, activity against Class A, Class B and Class D carbapenemases was 96.2%, 15.4% and 73.2%, respectively. In P. aeruginosa, imipenem/relebactam was active in 92.2% of isolates. By source of infection it was 94.8% in BSI, 92.9% in IAI, 91.7% in RTI, and 93.1% in UTI. An 88.7% of ICU isolates and 93.6% of non-ICU isolates were susceptible to imipenem/relebactam. Imipenem/relebactam remained active against P. aeruginosa ceftazidime-resistant (76.3%), cefepime-resistant (73.6%), imipenem-resistant (71.5%) and piperacillin-resistant (78.7%) isolates. Of all multidrug-resistant or difficult-to-treat resistance P. aeruginosa isolates, 75.1% and 46.2%, respectively, were susceptible to imipenem/relebactam. Conclusions. Imipenem/relebactam showed high rates of susceptibility in Enterobacterales and P. aeruginosa isolates from different sources of infection as well as depending on patients’ location (ICU or non-ICU scenarios)

Antimicrobial activity of ceftolozane-tazobactam against Enterobacterales and Pseudomonas aeruginosa recovered during the Study for Monitoring Antimicrobial Resistance Trends (SMART) program in Spain (2016-2018)

Objective: To analyse the susceptibility to ceftolozane-tazobactam and comparators in Enterobacterales and Pseudomonas aeruginosa isolates recovered from intraabdominal (IAI), urinary (UTI), respiratory (RTI) and bloodstream infection (BSI) in the SMART (Study for Monitoring Antimicrobial Resistance Trends) study. Methods: The susceptibility of 5,351 isolates collected in 11 Spanish hospitals (2016-2018) were analysed (EUCAST-2020 criteria) by broth microdilution and were phenotypically studied for the presence of extended-spectrum beta-lactamases (ESBL). Ceftolozane-tazobactam and/or carbapenem resistant isolates were genetically characterized for ESBL and carbapenemases. Results: Escherichia coli was the most frequent pathogen (49.3% IAI, 54.9% UTI, 16.7% RTI and 50% BSI), followed by Klebsiella pneumoniae (11.9%, 19.1%, 13.1% and 15.4%, respectively). P. aeruginosa was isolated in 9.3%, 5.6%, 32% and 9%, respectively. The frequency of isolates with ESBLs (2016-2017) was: 30.5% K. pneumoniae, 8.6% E. coli, 2.3% Klebsiella oxytoca and 0.7% Proteus mirabilis. Ceftolozane-tazobactam was very active against non-ESBL-(99.3% susceptible) and ESBL-(95.2%) producing E. coli being less active against K. pneumoniae (98% and 43.1%, respectively) isolates. CTX-M-15 was the most prevalent ESBL in E. coli (27.5%) and K. pneumoniae (51.9%) frequently associated with OXA-48-like carbapenemase. Overall, 93% of P. aeruginosa isolates were susceptible to ceftolozane-tazobactam, preserving this activity (>75%) in isolates resistant to other beta-lactams except in those resistant to meropenen or ceftazidime-avibactam. GES-5, PER-1, VIM-1/2 were the most prevalent enzymes in isolates resistant to ceftolozane-tazobactam. Conclusions: Ceftolozane-tazobactam showed high activity rates against isolates recovered in the SMART study although it was affected in K. pneumoniae and P. aeruginosa isolates with ESBL and/or carbapenemases

The CARBA-MAP study: national mapping of carbapenemases in Spain (2014–2018)

Introduction:Infections caused by carbapenem-resistant Enterobacterales (CRE) and carbapenem-resistant Pseudomonas aeruginosa, including isolates producing acquired carbapenemases, constitute a prevalent health problem worldwide. The primary objective of this study was to determine the distribution of the different carbapenemases among carbapenemase-producing Enterobacterales (CPE, specifically Escherichia coli, Klebsiella pneumoniae, Enterobacter cloacae complex, and Klebsiella aerogenes) and carbapenemase-producing P. aeruginosa (CPPA) in Spain from January 2014 to December 2018.Methods: A national, retrospective, cross-sectional multicenter study was performed. The study included the first isolate per patient and year obtained from clinical samples and obtained for diagnosis of infection in hospitalized patients. A structured questionnaire was completed by the participating centers using the REDCap platform, and results were analyzed using IBM SPSS Statistics 29.0.0.Results: A total of 2,704 carbapenemase-producing microorganisms were included, for which the type of carbapenemase was determined in 2692 cases: 2280 CPE (84.7%) and 412 CPPA (15.3%), most often using molecular methods and immunochromatographic assays. Globally, the most frequent types of carbapenemase in Enterobacterales and P. aeruginosa were OXA-48-like, alone or in combination with other enzymes (1,523 cases, 66.8%) and VIM (365 cases, 88.6%), respectively. Among Enterobacterales, carbapenemase-producing K. pneumoniae was reported in 1821 cases (79.9%), followed by E. cloacae complex in 334 cases (14.6%). In Enterobacterales, KPC is mainly present in the South and South-East regions of Spain and OXA-48-like in the rest of the country. Regarding P. aeruginosa, VIM is widely distributed all over the country. Globally, an increasing percentage of OXA-48-like enzymes was observed from 2014 to 2017. KPC enzymes were more frequent in 2017–2018 compared to 2014–2016.Discussion: Data from this study help to understand the situation and evolution of the main species of CPE and CPPA in Spain, with practical implications for control and optimal treatment of infections caused by these multi-drug resistant organisms

Distinct epidemiology and resistance mechanisms affecting ceftolozane/tazobactam in Pseudomonas aeruginosa isolates recovered from ICU patients in Spain and Portugal depicted by WGS

STEP and SUPERIOR study groups.[Objectives] To analyse the epidemiology, the resistome and the virulome of ceftolozane/tazobactam-susceptible or -resistant Pseudomonas aeruginosa clinical isolates recovered from surveillance studies in Portugal (STEP, 2017–18) and Spain (SUPERIOR, 2016–17).[Methods] P. aeruginosa isolates were recovered from intra-abdominal, urinary tract and lower respiratory tract infections in ICU patients admitted to 11 Portuguese and 8 Spanish hospitals. MICs were determined (ISO-standard broth microdilution, EUCAST 2020 breakpoints). A subset of 28 ceftolozane/tazobactam-resistant P. aeruginosa isolates were analysed and compared with 28 ceftolozane/tazobactam-susceptible P. aeruginosa strains by WGS.[Results] Clonal complex (CC) 235 (27%) and CC175 (18%) were the most frequent, followed by CC244 (13%), CC348 (9%), CC253 (5%) and CC309 (5%). Inter-hospital clonal dissemination was observed, limited to a geographical region (CC235, CC244, CC348 and CC253 in Portugal and CC175 and CC309 in Spain). Carbapenemases were detected in 25 isolates (45%): GES-13 (13/25); VIM type (10/25) [VIM-2 (4/10), VIM-20 (3/10), VIM-1 (2/10) and VIM-36 (1/10)]; and KPC-3 (2/25). GES-13-CC235 (13/15) and VIM type-CC175 (5/10) associations were observed. Interestingly, KPC-3 and VIM-36 producers showed ceftolozane/tazobactam-susceptible phenotypes. However, ceftolozane/tazobactam resistance was significantly associated with GES-13 and VIM-type carbapenemase production. Six non-carbapenemase producers also displayed ceftolozane/tazobactam resistance, three of them showing known ceftolozane/tazobactam resistance-associated mutations in the PBP3 gene, ftsI (R504C and F533L). Overall, an extensive virulome was identified in all P. aeruginosa isolates, particularly in carbapenemase-producing strains.[Conclusions] GES-13-CC235 and VIM type-CC175 were the most frequent MDR/XDR P. aeruginosa clones causing infections in Portuguese and Spanish ICU patients, respectively. Ceftolozane/tazobactam resistance was mainly due to carbapenemase production, although mutations in PBP-encoding genes may additionally be involved.The study was funded by MSD Portugal (protocol VP6918) and MSD Spain (protocol MSD-CEF-2016-01). This study was also supported by Plan Nacional de I + D + i 2013–16 and Instituto de Salud Carlos III, Subdirección General de Redes y Centros de Investigación Cooperativa, Ministerio de Economía, Industria y Competitividad, Spanish Network for Research in Infectious Diseases [RD16/0016/0001, RD16/0016/0004, RD16/0016/0006, RD16/0016/0007, RD16/0016/0010 and REIPI RD16/0016/0011], co-financed by the European Development Regional Fund ‘A way to achieve Europe’ (EDRF), Operative Program Intelligent Growth 2014–20. M.H.-G. is supported by a research contract from a European Project [IMI-JU-9–2013, Ref. iABC - 115721–2].Peer reviewe

Presence of Chromosomal <i>crpP</i>-<i>like</i> Genes Is Not Always Associated with Ciprofloxacin Resistance in <i>Pseudomonas aeruginosa</i> Clinical Isolates Recovered in ICU Patients from Portugal and Spain

CrpP enzymes have been recently described as a novel ciprofloxacin-resistance mechanism. We investigated by whole genome sequencing the presence of crpP-genes and other mechanisms involved in quinolone resistance in MDR/XDR-Pseudomonas aeruginosa isolates (n = 55) with both ceftolozane-tazobactam susceptible or resistant profiles recovered from intensive care unit patients during the STEP (Portugal) and SUPERIOR (Spain) surveillance studies. Ciprofloxacin resistance was associated with mutations in the gyrA and parC genes. Additionally, plasmid-mediated genes (qnrS2 and aac(6′)-Ib-cr) were eventually detected. Ten chromosomal crpP-like genes contained in related pathogenicity genomic islands and 6 different CrpP (CrpP1-CrpP6) proteins were found in 65% (36/55) of the isolates. Dissemination of CrpP variants was observed among non-related clones of both countries, including the CC175 (Spain) high-risk clone and CC348 (Portugal) clone. Interestingly, 5 of 6 variants (CrpP1-CrpP5) carried missense mutations in an amino acid position (Gly7) previously defined as essential conferring ciprofloxacin resistance, and decreased ciprofloxacin susceptibility was only associated with the novel CrpP6 protein. In our collection, ciprofloxacin resistance was mainly due to chromosomal mutations in the gyrA and parC genes. However, crpP genes carrying mutations essential for protein function (G7, I26) and associated with a restored ciprofloxacin susceptibility were predominant. Despite the presence of crpP genes is not always associated with ciprofloxacin resistance, the risk of emergence of novel CrpP variants with a higher ability to affect quinolones is increasing. Furthermore, the spread of crpP genes in highly mobilizable genomic islands among related and non-related P. aeruginosa clones alert the dispersion of MDR pathogens in hospital settings

Risk Factors and Outcomes for Multidrug Resistant Pseudomonas aeruginosa Infection in Immunocompromised Patients

Background: Pseudomonas aeruginosa (PSA) infection often occurs in immunocompromised patients, which also face an increased risk of multidrug-resistant (MDR) bacteria. A deeper knowledge of the risk factors for MDR-PSA infection in this patient population may help to choose appropriate empirical antibiotic therapy. Methods: a single-center case-control (1:2) retrospective study that included 48 patients with underlying immunosuppression developing MDR-PSA infection (cases) and 96 patients also immunocompromised that were infected with non-MDR-PSA (controls) was conducted. Both groups were matched by site of infection, clinical features and type of immunosuppression. Risk factors for MDR-PSA were assessed by logistic regression. Clinical outcomes were also compared between both groups. Results: immunosuppression was due to solid cancer in 63 (43.8%) patients, solid organ transplantation in 39 (27.1%), hematological disease in 35 (24.3%) and other causes in 7 (4.9%). Independent risk factors for MDR-PSA infection were diabetes mellitus (odds ratio [OR]: 4.74; 95% confidence interval [CI]: 1.63&ndash;13.79; p = 0.004), antibiotic therapy in the previous 3 months (OR: 5.32; 95% CI: 1.93&ndash;14.73; p = 0.001), previous MDR-PSA colonization (OR: 42.1; 95% CI: 4.49&ndash;394.8; p = 0.001) and septic shock (OR: 3.73; 95% CI: 1.36&ndash;10.21; p = 0.010). MDR-PSA cases were less likely to receive adequate empirical therapy (14 [29.2%] vs. 69 [71.9%]; p &lt; 0.001). 30-day clinical improvement was less common in MDR-PSA cases (25 [52.1%] vs. 76 [79.2%]; p = 0.001). Conclusions: diabetes mellitus, previous MDR-PSA colonization, prior receipt of antibiotics and septic shock acted as risk factors for developing MDR-PSA infections in immunocompromised patients, who have a poorer outcome than those infected with non-MDR-PSA strains

Activity of ceftolozane/tazobactam against Pseudomonas aeruginosa and Enterobacterales isolates recovered from intensive care unit patients in Spain: The SUPERIOR multicentre study

Patients in intensive care units (ICUs) present a high risk of developing an infection caused by multidrug-resistant bacteria. Consequently, new antimicrobials and combinations are required. In this study, the activity of ceftolozane/tazobactam (C/T) was evaluated against Enterobacterales (n = 400) and Pseudomonas aeruginosa (n = 80) clinical isolates collected from patients in Spanish ICUs with complicated urinary tract infections (cUTI) and complicated intra-abdominal infections (cIAI). Overall susceptibility to C/T in P. aeruginosa isolates by infection type was 95.7% in cUTI (MIC50/90, 1/4 mg/L) and 85.3% in cIAI (MIC50/90, 1/64 mg/L). Activity against P. aeruginosa was maintained regardless of its resistance pattern, confirming that C/T is one of the best antipseudomonal agents along with colistin and amikacin. Susceptibility to C/T in Enterobacterales by infection type was 79.5/81.9% and 89.3/92.3% (EUCAST/CLSI) in cIAI and cUTI isolates, respectively. Activity was excellent against wild-type organisms, with 100% susceptible and inhibited at MIC ≤1 mg/L. Nevertheless, C/T susceptibility decreased against extended-spectrum β-lactamase (ESBL)-producing isolates: Escherichia coli (80.4/84.8% susceptible by EUCAST/CLSI) and Klebsiella pneumoniae (59.1/77.3% susceptible by EUCAST/CLSI). No activity of C/T was observed in carbapenemase-producing isolates. The in vitro activity of C/T observed in this surveillance study suggests that this agent can be considered as a therapeutic option for cUTI and cIAI due to Enterobacterales and P. aeruginosa in ICU patients, particularly when carbapenemase-producing isolates are not involved.This study was funded by MSD Spain and was supported by Plan Nacional de I+D+i 2013–2016 and Instituto de Salud Carlos III, Subdirección General de Redes y Centros de Investigación Cooperativa, Ministerio de Economía, Industria y Competitividad, Spanish Network for Research in Infectious Diseases [RD16/0016/0001, RD16/0016/0004, RD16/0016/0006, RD16/0016/0007, RD16/0016/0010 and REIPI RD16/0016/0011], co-financed by the European Development Regional Fund ‘A way to achieve Europe’ (ERDF), Operative program Intelligent Growth 2014–2020. SG-F is supported by a research contract from Instituto de Salud Carlos III, Spain [Rio Hortega program, ref. CM17/00033]

Seguimiento de la sensibilidad antimicrobiana de microorganismos gramnegativos procedentes de infecciones intraabdominales y urinarias del estudio SMART (España, 2016 y 2017)

[EN] Introduction: Continuous antimicrobial resistance surveillance is recommended by Public Health authorities. We up-dated data from the SMART (Study for Monitoring Antimicrobial Resistance Trends) surveillance study in Spain.-- Material and methods: The antimicrobial susceptibility data and extended-spectrum beta-lactamase (ESBL) production in isolates recovered from intra-abdominal (IAI) (n=1,429) and urinary tract (UTI) (n=937) infections during the 2016- 2017 SMART study in 10 Spanish hospitals were analysed.-- Results: Escherichia coli was the most frequently microorganism isolated (48.3% and 53.7%) followed by Klebsiella spp. (11.5% and 21.9%) in IAIs and UTIs, respectively. Figures for Pseudomonas aeruginosa were 9.0% and 6.1%, being more frequently recovered from patients with nosocomial infections. Overall, 9.9% (IAI) and 14.0% (UTI) of E. coli, Klebsiella spp. and Proteus mirabilis isolates were ESBL-producers, being Klebsiella pneumoniae (34.5%) from UTI of nosocomial origin the most frequent. ESBL-producers were higher in patients >60 years in both IAIs and UTIs. As in previous years, amikacin (96.3%-100% susceptibility), ertapenem (84.2%-100%) and imipenem (70.3%- 100%) were the most active antimicrobials tested among Enterobacterales species. The activity of amoxicillin-clavulanic, piperacillin-tazobactam, and ciprofloxacin susceptibility was lower, particularly among ESBL-producers. Ertapenem susceptibility (88.9%-100%) was retained in ESBL-E. coli isolates that were resistant to these antimicrobials but decreased (28.6%-100%) in similar isolates of K. pneumoniae.-- Conclusions: Continuous antimicrobial resistance surveillance from the SMART study reveals overall maintenance of ESBL-producers in Spain, although with higher presence in isolates from UTIs than from IAIs. Moreover, ertapenem activity was high in E. coli irrespective of ESBL production but decreased in K. pneumoniae, particularly among ESBL-producers.[ES] Introducción: Las autoridades de Salud Pública recomiendan la vigilancia continua de la resistencia a los antimicrobianos. Se actualizan los datos del estudio SMART (Study for Monitoring Antimicrobial Resistance Trends) en España.-- Material y métodos: Se analizaron los datos de sensibilidad antimicrobiana y la producción de betalactamasas de espectro extendido (BLEE) en aislamientos obtenidos en el estudio SMART de infecciones intraabdominales (IIA) (n=1.429) y del tracto urinario (ITU) (n=937) durante 2016-2017 en 10 hospitales españoles.-- Resultados: Escherichia coli fue el microorganismo más frecuente (54,5% y 57,5%, respectivamente), seguido de Klebsiella spp. (18,4% y 25,4%) en IIA y en ITU. En Pseudomonas aeruginosa estas cifras fueron 9% y 6%, siendo más frecuente en la infección nosocomial. El 9,9% (IIA) y el 14% (ITU) del to-tal de los aislados de E. coli, Klebsiella spp. y Proteus mirabilis producían BLEE, obteniéndose la tasa más alta en Klebsiella pneumoniae (34.5%) en ITU nosocomial. El mayor porcentaje de aislados con BLEE se observó en pacientes >60 años, tanto en IIA como en ITU. Como en años anteriores, amikacina (sensibilidad 96,3%-100%), ertapenem (84,2%-100%) e imipenem (70,3%-100%) fueron los antimicrobianos más activos en Enterobacterales. La sensibilidad a amoxicilina-ácido clavulánico, piperacilina-tazobactam y ciprofloxacino fue menor, en particular en los productores de BLEE. La sensibilidad a ertapenem (88,9%-100%) se mantuvo en E. coli con BLEE resistente a estos antimicrobianos, pero disminuyó (28,6%-100%) en aislados similares de K. pneumoniae.-- Conclusiones: La vigilancia continua de la resistencia a los antimicrobianos en el estudio SMART revela el mantenimiento de la frecuencia de aislados productores de BLEE en España, pero con mayor presencia en las ITUs que en las IIAs. Además, la sensibilidad a ertapenem fue alta en E. coli con independencia de la producción de BLEE, pero disminuyó en K. pneumoniae, sobre todo en los productores de BLEE.Rafael Cantón has collaborated in educational meetings sponsored by MSD and Pfizer. He has also had research grants from MSD. F. Javier Castillo has collaborated in educational meetings sponsored by MSD.Peer reviewe